p-sulfamyl beta-hydroxyethyl carbanilate diuretic compositions



I p-SULFAMYL fi-HYDROXYETHYL CARBANILATE DIURETIC COMPOSITIONS Robert G. Sanders, Pompton Lakes, and Roland R. Read,

Morristown, NJ., and Richard J. Palazzolo, Northbrook, Ill.

No Drawing. Filed Sept. 5, 1957, Ser. No. 682,076

3 Claims. (Cl. 167-65) This invention relates to therapeutic compositions and more particularly to therapeutic compositions which are efiective to inhibit carbonic anhydrase activity.

This application is a continuation-in-part of our application Serial Number 456,639, filed September 16, 1954, now abandoned, and of copending application Serial Number 532,113, filed September 1, 1955, now US. Patent No. 2,920,012.

Briefly, the present invention is directed to therapeutic compositions comprising a compound having the formula:

NHCOOR wherein R is ethyl, fl-hydroxy ethyl and allyl, and a pharmaceutical carrier. Of the above-noted compounds, we preferably employ p-sulfarnyl fi-hydroxy ethyl carbanilate.

Among the several objects of the invention may be noted the provision of therapeutic compositions and methods which are effective to inhibit the activity of the enzyme carbonic anhydrase; the provision of such therapeutic compositions which are effective diuretic compositions; and the provision of therapeutic compositions of the class described which are stable and nontoxic. Other objects and features will be in part apparent and in part pointed out hereinafter.

The invention accordingly comprises the products and methods hereinafter described, the scope of the invention being indicated in the following claims.

The enzyme carbonic anhydrase plays an important role in the acidification of the urine through its catalysis of the reversible reaction:

The carbonic acid so form yields hydrogen and bicarbonate ions through the reversible reaction:

Thus, carbonic anhydrase activity indirectly determines the number of hydrogen ions which are available to replace sodium ions in buffer compounds from the blood, such as, for example, disodium phosphate and sodium bicarbonate. The sodium ions thus replaced are conserved and return to the blood, and carbonic acid formed in the above reaction catalyzed by carbonic anhydrase also returns to the blood.

In accordance with the present invention, it has been found that carbonic anhydrase activity can be effectively inhibited and the excretion of water, sodium and potassium in the urine increased by the use of therapeutic 2,967,130 Patented Jan. 3, 1961 compositions including a p-sulfamyl carbanilate compound having the following formula:

I SOZNHQ NHCOOR wherein R is ethyl, B-hydroxy ethyl or allyl. The inhibition of carbonic anhydrase activity by the compositions of the present invention results in a reduction of hydrogen ions available for the acidification of the urine. As a consequence, the pH of the urine increases, fewer sodium ions of the buffer compounds are replaced by hydrogen ions, and larger amounts of sodium, chloride and bicarbonate are excreted in the urine. Further, because the formation of carbonic acid from carbon dioxide and water is inhibited, water excretion is increased. Thus, the diuretic action provided by the compositions of the invention is useful to relieve edema, for example, caused by congestive heart failure or other causes.

The p-sulfamyl carbanilate compounds specified herein are not only compatible with other components employed in therapeutic compositions, "but they are also stable and nontoxic. For example, intraperitoneal doses of p-sulfamyl fl-hydroxy ethyl carbanilate up to 1600 mg./ kg. were tolerated by male White rats, and only three animals out of a group of nine receiving 1800 mg./kg. intraperitoneally died. Moreover, oral doses up to 1500 mg./kg. of this carbanilate compound did not produce any ill effect in male white rats. Three groups of white rats, with six animals in each group, received 600, 900 and 1200 mg./kg. respectively of p-sulfamyl fl-hydroxy ethyl carbanilate per day for twelve days and showed a normal gross pathology after being sacrificed and autopsied on the thirteenth day.

The carbanilate compounds of the novel therapeutic compositions of the invention have the formula:

NHCOOR wherein R represents ethyl, fl-hydroxy ethyl or allyl. The therapeutic compositions of the present invention comprise a compound of the above-mentioned class and a pharmaceutical carrier which may be either a liquid or solid material. 'It is preferred that the pharmaceutical carrier be a solid material such as, for example, starch, gelatin, lactose, talc, calcium stearate or the like. Any of the pharmaceutical carriers conventionally used in therapeutic compositions may be utilized where such materials are compatible with the aforementioned carbanilate compounds. These compositions include tablets, capsules and the like, and may include a liquid pharmaceutical carrier and be in the form of solutions, dispersions, suspensions, elixirs and the like.

The percentage of the carbanilate compound incorporated in the therapeutic compositions of the invention may be varied considerably. Exemplary compositions may contain approximately by weight of one of the above-mentioned carbanilate compounds, although greater or smaller amounts than 80% may also be used in the practice of the invention. The daily dosage administered to a patient may also vary considerably, depending upon the patients condition and the amount prescribed by the physician in charge. In the case of Example Therapeutic diuretic tablets were prepared having the following composition:

Component G. p-Sulfamyl fl-hydroxy ethyl carbanilate 0.5 Corn starch, U.S.P 0.1 Calcium stearate 0.005

The tablets were prepared by grinding the p-sulfamyl 3 hydroxy ethyl carbanilate through a No. 24 screen, adding the corn starch and calcium stearate and, after thoroughly mixing the components, compressing into tablets.

It will be understood, of course, that the therapeutic p itio s of t invention ma b mpl ed in the treatment of any condition Where the inhibition of earbonic anhydrase activity will produce a beneficial result.

In viewvof the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As various changes could be made in the above products and methods without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

' We claim:

1. A therapeutic composition useful as a diuretic comprising a dosage form of p-sulfamyl fi-hydroxy ethyl carbanilate in combination with a pharmaceutical carrier.

2. A therapeutic composition useful as a diuretic comprising a dosage unit form of p-sulfamyl B-hydroxy ethyl carbanilate in combination with a solid pharmaceutical carrier.

3. A therapeutic composition useful as a diuretic comprising a dosage unit form of p-sulfamyl fi-hydroxy ethyl carbanilate in combination with a liquid pharmaceutical carrier.

References Cited in the file of this patent UNITED STATES PATENTS 2,789,938 Wilcox et 1. Apr. 23, 1957 OTHER REFERENCES 'J.A.C.S., 72, pp. 4893-4896, November 1950. Chem. Abst., 41, pp. 4809:4811, 1947. I.A.M.A., 151:16, p. 1430, April 18, 1953. 

1. A THERAPEUTIC COMPOSITION USEFUL AS A DIURETIC COMPRISING A DOSAGE FROM OF P-SULFAMYL B-HYDROXY ETHYL CARBANILATE IN COMBINATION WITH A PHARMACEUTICAL CARRIER. 